PKR has a well-established and extensively investigated role in innate immunity, serving as an intracellular receptor for virally-derived dsRNAs. By phosphorylating eIF-21, PKR can block host cell translation to limit the impact of viral infection. Although PKR is generally thought to perform its role in immunosurveillance in the cytoplasm, it also localizes to the nucleolus. The nuclear function of PKR is unknown but may have extensive relevance to innate immunity, other pathological conditions, and normal biology. Considerable preliminary biochemical data described herein indicate that the nuclear function of PKR is dependent on its dsRNA-binding capacity and involves interplay with the PARP1 cohort. Specifically, these data suggest that the nucleus may be the source of novel PKR ligands, including dsRNA and the enzymatic product of PARP1, poly(ADP-ribose). Moreover, these ligands are not expected to be limited to the nucleolus and may mark much of the human genome. This proposal seeks to characterize an unappreciated pathway by which nuclear ligands co-opt PKR to participate in the response to DNA-damage and potentially other cellular insults.